tbuckley/cabot-search huggingface dataset:
CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY TO EVALUATE ATEZOLIZUMAB IN COMBINATION WITH CABOZANTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Shiao-Pei Weathers, Carlos Kamiya-Matsuoka, Nazanin Majd, Alda Ashu, Chantell Thompson, Evguenia Gachimova, Ashley Aaroe, Chirag Patel, Monica Loghin, Barbara O'Brien, W K Alfred Yung, Vinay Puduvalli, John de Groot
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of glioblastoma (GBM) in both newly diagnosed and recurrent disease which underscores the need for rational combinatorial strategies. Atezolizumab is a humanized monoclonal antibody that targets PD-L1 and has been shown to enhance the magnitude of tumor-specific T cell responses. Combining PD-L1/PD-1 axis inhibition with targeted therapy like cabozantinib which has both anti-tumoral and immunomodulatory properties may result in synergistic effects. Cabozantinib may modulate the myeloid cell population to overcome resistance to anti-PD-1/PD-L1 therapy. METHODS Eligibility criteria were those with recurrent GBM, age &amp;gt;18 yrs with 1st or 2nd recurrence who were naïve to antiangiogenic and receptor tyrosine kinase inhibitor treatment. The primary objective of the phase I run-in was to evaluate the safety of atezolizumab in combination with cabozantinib. RESULTS 1 dose-limiting toxicity (DLT) of a grade 3 ALT elevation was observed in the first 6 DLT evaluable patients treated during the safety run-in phase. Regarding immune related adverse events, 1 of 6 patients developed atezolizumab-related grade 1 hypothyroidism. 1 of 6 patients developed study treatment-related grade 2 diarrhea. 2 patients after completion of 2 cycles of treatment had evidence of a partial radiographic response ( &amp;gt; 50% decrease). 1 patient had a near partial radiographic response (45% decrease). 2 patients had stable disease after completion of 2 cycles of the combinatorial treatment. 1 patient had only completed the first 28-day cycle, DLT period, and had not yet had imaging to reassess disease status. CONCLUSIONS The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM patients, radiographic responses were observed. The phase II component of the trial is recruiting patients (n = 45) to evaluate clinical efficacy. Multi-omic correlative studies and fecal microbiome analyses are planned.
PATH-23. CLINICOPATHOLOGIC ANALYSIS OF NOVEL METHYLATION CLUSTERS OF IDH-WILDTYPE DIFFUSE GLIOMAS
Authors: Omkar Singh, Kenneth Aldape, Zied Abdullaev, Rust Turakulov, Felipe Andreiuolo, Felipe D'Almeida Costa, Sandra Camelo-Piragua, Peter Pytel, Daniel Zhang, Ewa Borys, Stephen Nix, Igor Fernandes, Emily Sloan, Kester Phillips, Luciano Neder Serafini, Jorge Trejo-Lopez, Joe Mendez, Charles Eberhart, Matthew Smith-Cohn, Stewart Neill, Brock Christensen, Robert Macaulay, Howard Colman, Aivi Nguyen, Caterina Giannini, Rong Li, James Mandell, Tobias Kessler, Wolfgang Wick, Chris Jones, Matthew Clarke, Alan MacKay, Jeffrey Helgager, Han Lee, Giselle Lopez, Arie Perry, Saman Ahmadian, Mohammad Haeri, Shih-Hsiu Wang, Sonika Dahiya, Andrea Souza, Joao Vitor Antunes Marques Gregorio, Hugo Sterman, MacLean P Nasrallah, Orwa Aboud
Journal: Neuro-Oncology (2023)

Abstract Methylation profiling of brain tumors has revealed novel clusters whose biological and clinical significance is unknown. These include three entities termed by the 12.5 version of the Heidelberg methylation classifier as adult-type diffuse high grade glioma, IDH-wildtype, subtype B (HGG_B), subtype E (HGG_E), and subtype F (HGG_F). We have identified 75 cases belonging to these groups: HGG_B (25 cases, 32% female), HGG_E (40 cases, 42% female), and HGG_F (18 cases, 33% female). Although originally characterized as “adult-type,” we find that 70% of HGG_E cases are pediatric, with a median age at diagnosis of 11 years. HGG_B cases are predominantly seen in young adults, and HGG_F in older adults. The histology varies among methylation classes, with HGG_B cases demonstrating high-grade, predominantly astrocytic, morphology, while HGG_E cases demonstrate high-grade glial histology with distinct nuclear features, and HGG_F cases show highly infiltrative but lower grade glial morphology. Patient outcome data obtained to date shows a collective median survival exceeding 5 years, suggesting re-consideration of the proposed grading for these tumors. MGMT promoter methylation differs across the HGG_B (0%), HGG_E (12%), and HGG_F (0%) subtypes. Mutational analyses show enrichment of TERT promoter mutations in the HGG_F group, while HGG_E samples are enriched for tumors with POLE mutations and elevated tumor mutation burden. HGG_E tumors show epigenetic similarity to pediatric high-grade diffuse gliomas (pedHGG_RTK1A); we therefore propose that HGG_E be considered a pediatric-type HGG. HGG_B tumors show demographic and genomic similarities to high-grade astrocytomas with piloid features, including a subset of cases with CDKN2A/2B loss and ATRX mutation. HGG_F separate into two groups dictated by brain location, and despite the presence of TERT promoter mutations, appear distinct from GBMs. Overall, our work represents an initial effort to understand the morphologic, genomic and clinical characteristics of these previously uncharacterized subtypes of gliomas.
ANGI-02. CELL MIGRATION SIMULATOR-BASED BIOMARKERS FOR GLIOBLASTOMA
Authors: Jay Hou, Mariah McMahon, Tyler Jubenville, Clark Chen, Jann Sarkaria, David Odde
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is the most aggressive malignant brain tumor with the poor survival due to its invasive nature driven by cell migration. There is still no effective treatment targeting glioma cell migration based on their transcriptomic information, due to the lack of understanding in the links to the fundamental mechanics of cell migration. In the previous studies, we developed a physics-based motor-clutch model, the cell migration simulator (CMS), to identify the basic mechanisms of cell migration in various cell types. In this study, we found that glioblastoma patient-derived (xenograft) (PD(X)) cell lines across mesenchymal (MES), proneural (PN), classical (CL) subtypes and two institutions (N = 13 patients) had optimal motility and traction force on stiffnesses around 9.3kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. We applied the CMS as a consistent framework to describe the physical parameters of glioblastoma patient cell migration. Using single cell migration and force generation data on compliant 2D surfaces, we found all glioma PD(X) lines (11 patients) had balanced myosin/adhesion ratios resulting in effective migration. Mesenchymal (MES) lines had enhanced F-actin polymerization resulting in higher motility. Adherent PDX lines had increased myosin-adhesion amount resulting in higher traction force. The CMS also predicted the differential cell migration under cytoskeletal drugs between glioma subtypes. Finally, we found 18 genes in actin cytoskeleton and focal adhesion pathways significantly correlated with the glioma physical parameters, which were being used to estimate the physical parameters of a larger cohort (66 patients) and to strategize targeting their cell migration. Overall, we described a consistent physics-based framework for parameterizing individual glioblastoma patients, connecting to clinical transcriptomic data, and predicting drug effects, that can potentially be used to develop subtype and patient-specific anti-migratory therapeutic strategies.
CTIM-24. REPEATED PERIPHERAL INFUSIONS OF ANTI-EGFRVIII CAR T CELLS IN COMBINATION WITH PEMBROLIZUMAB REMODELS THE TUMOR MICROENVIRONMENT IN DE NOVO GLIOBLASTOMA
Authors: Zev Binder, Stephen J Bagley, Lamia Lamrani, Eliana Marinari, Arati Desai, MacLean P Nasrallah, Eileen Maloney, Steven Brem, Robert A Lustig, Goldie Kurtz, Michelle Alonso-Basanta, Pierre-Emmanuel Bonte, Christel Goudot, Wilfrid Richer, Eliane Piaggio, Shawn Kothari, Lea Guyonnet, Coralie Guerin, Joshua Waterfall, Suyash Mohan, Wei-Ting Hwang, Oliver Tang, Meghan Logun, Meghna Bhattacharyya, Kelly Markowitz, Devora Delman, Amy Marshall, E John Wherry, Sebastian Amigorena, Gregory Beatty, Jennifer Brogdon, Elizabeth Hexner, Denis Migliorini, Cecile Alanio, Donald M O'Rourke
Journal: Neuro-Oncology (2023)

Abstract Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n = 7). Treatment was well tolerated without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9 – 6.0 months) and overall survival of 11.8 months (90 % CI, 9.2 – 14.2 months). We aimed to elucidate reasons for limited efficacy through correlative analyses. Using BBZ qPCR, we found circulating CAR T cells in 5 out of 7 patients at the time of repeat resection, but only in one patient in the tumor. However, shared TCRs were found between the infusion product and the relapsed tumors, which could indicate an infiltration but lack of persistence of the CART. We further compared the tumor microenvironment of the tumors harvested before and after CAR+aPD1 administration using single cell RNAseq, and observed comparable proportions of the major immune cell subsets. However, the myeloid and T cells infiltrating the tumors significantly evolved, with more exhausted, regulatory and IFN-stimulated T cells at the relapse. At that time, the amount of IFN-stimulated T cells positively correlated with time from relapse to death. Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.
PATH-37. PROGNOSTIC IMPACT OF TUMOR MUTATIONAL BURDEN AT BASELINE IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Dohoon Park, Hwan Park, Yongjae Kim, Kang-Seo Park, Ji Eun Park, Chang Ohk Sung, Shinkyo Yoon, Ho-Su Lee
Journal: Neuro-Oncology (2023)

Abstract Tumor mutational burden (TMB) has emerged as a potential biomarker for survival and response to immune checkpoint therapy. However, limited data are available regarding the prognostic impact of TMB at baseline in glioblastoma (GBM). This study aimed to evaluate the somatic mutation status and survival outcomes of isocitrate dehydrogenase (IDH) wildtype GBM using a dataset of GBM samples from cBioPortal and single tertiary hospital. A total of 840 samples were extracted from cBioPortal, including 410 samples from Memorial Sloan Kettering Cancer Center (MSKCC), 234 samples from The Cancer Genome Atlas (TCGA), 106 samples from Glioma Longitudinal Analysis Consortium (GLASS), and 90 samples from Clinical Proteomic Tumor Analysis Consortium (CPTAC). Additionally, we enrolled 341 GBM patients with targeted sequencing data (OncoPanel AMC) from Asan Medical Center. The TMBHigh group was defined as the top 10% value of TMB within each cohort. Among the total of 1,081 IDH-wt GBM samples, 104 samples were classified as TMBHigh. No significance difference in overall survival (OS) was observed between the TMBHigh group and the non-TMBHigh group across the 5 cohorts. The mutations of DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and POLE) was significantly higher in the TMBHigh group compared with the non-TMBHigh group in 3 of 5 cohorts (pASAN=1.02x10-4, pMSKCC=1.5x10-2, and pCPTAC=1.26x10-2). However, when we calculated the indel to total mutation ratio (I-index) to dedect microsatellite Instability, only the MSKCC cohort showed a higher I-index in the TMBHigh group compared to the non-TMBHigh group (16.7% vs 13.7%, p=2.67x10-3). In summary, there is no significant association between TMB at baseline and poor survival outcomes in IDH-wildtype GBM. Further research is needed to explore the potential implications of TMB as a prognostic marker and its relevance for personalized treatment strategies in GBM patients.
TMET-14. PROBING TCA CYCLE ACTIVITY IN H3WT AND H3K27M-ALTERED DIFFUSE MIDLINE GLIOMAS
Authors: Omkar Ijare, Jackson Roberson, Sushmita Kumar, Rishith Ramamurthy, David S Baskin, Kumar Pichumani
Journal: Neuro-Oncology (2023)

Abstract DMG has high levels of α-ketoglutarate (α-KG), causing histone hypomethylation and promoting tumor growth. Therefore, targeting α-KG production in DMG tumors may be of therapeutic value. α-KG is synthesized in the tricarboxylic acid cycle (TCA) cycle via oxidation of multiple nutrients including glucose and glutamine. Hence, probing mitochondrial metabolism in DMG with the goal of altering α-KG levels will lead to new therapies to treat DMG. Here, we examine glucose and glutamine metabolism in H3WT and H3K27M-altered patient-derived DMG cells (Dr. Monje’s lab) using GC-MS based metabolic flux analysis. Both cells were grown as neurospheres in tumor stem medium. Neurospheres were treated with 11.0 mM [U-13C]glucose or 4.0 mM [U-13C]glutamine. The 13C-isotopomer analysis revealed that H3K27M-altered cells produced higher levels of (M+3) pyruvate (14.05 ± 5.37% vs. 7.15 ± 2.98%), and (M+3) lactate (9.46 ± 6.48 % vs.3.87 ± 1.80 %) compared to the H3WT. Whereas, the glucose derived (M+2) citrate in the TCA cycle was similar in both cases (15.81 ± 2.91% vs. 16.76 ± 4.15%). This data shows that both types of DMG possess similar TCA cycle activity leading to the synthesis of α-KG, which we measured through glutamate 13C labeling. Next, we probed [U-13C]glutamine metabolism in these two types of DMG cells as glutamine is another major source of α-KG synthesis . Both cell lines showed higher levels of glutamine-derived M+5 α-KG (34.62 ± 2.12 % vs. 42.17 ± 5.05%). Interestingly, H3K27M-altered DMG showed higher flux via reductive carboxylation generating M+5 citrate when compared to M+4 citrate produced via canonical glutamine metabolism in the TCA cycle (citrate M+5: 7.13 ± 2.14% vs. 4.33 ± 1.68%; citrate M+4: 4.04 ± 1.06% vs. 7.85 ± 1.52%). Therefore, inhibiting synthesis of α-KG in H3 K27M-altered DMGs would be of therapeutic interest in the treatment of both DMG subtypes.
INNV-16. COMPARISON OF SURVIVAL OUTCOMES OF RECURRENT GLIOBLASTOMA PATIENTS: A COMPARISON BETWEEN PATIENTS ENROLLED INTO CLINICAL TRIALS AND PATIENTS THAT DID NOT ENROLL INTO TRIALS AT FIRST PROGRESSION
Authors: Geethanjali Balasubramanian, Shruti Yerramothu, Gilbert Youssef, Eudocia Lee, Luis Nicolas Gonzalez Castro, Jose Ricardo McFaline-Figueroa, Lakshmi Nayak, David Reardon, Lorenzo Trippa, Patrick Wen, Rifaquat Rahman
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Clinical trials in neuro-oncology use stringent eligibility criteria to select patients. We examined potential differences of survival outcomes in recurrent glioblastoma patients participating in clinical trials compared to trial-eligible patients treated outside of a trial. METHODS We reviewed 378 adult IDH-wild-type glioblastoma patients treated for first recurrence at our institution 2014-2020. We retrospectively evaluated patients for clinical trial eligibility based upon review of performance status, laboratory values (e.g. comprehensive metabolic panel, complete blood count), and other common eligibility criteria. Overall survival was defined as time from date of first recurrence to death. Cox proportional hazards modeling were used to evaluate outcomes of trial eligible patients compared to patients who received treatment on a clinical trial. RESULTS Among 378 patients, 171 patients (47%) enrolled onto a trial at first recurrence. Amongst 207 non-trial patients, 65 patients were excluded due to ineligibility or missing data. The primary reasons for trial ineligibility was known additional malignancy, thrombocytopenia, KPS &amp;lt; 60, active autoimmune disease, and presence of diffuse leptomeningeal disease. There were 142 (69%) patients deemed trial-eligible per our retrospective screening. In trial-eligible non-trial and trial participants (N=313), trial participation was associated with improved survival (Adjusted-HR 0.58, 95%CI 0.43-0.77, p&amp;lt; 0.001) after adjustment for age (HR 1.02, 95%CI:1.01-1.03, p=0.01), MGMT promoter methylation (HR 0.64, 95%CI:0.47-0.88, p=0.008), KPS at first recurrence (HR 0.99, 95%CI:0.97-1.00, p=0.02), time to first recurrence (HR 1.00, 95%CI:0.999-1.00, p=0.07), surgery at first recurrence (HR 0.96, 95%CI:0.72-1.27, p=0.77), standard 6 weeks radiation upfront (HR 0.47, 95%CI:0.25-0.87, p=0.02), and concurrent temozolomide use upfront (HR 0.71, 95%CI:0.43-1.15, p=0.18). CONCLUSION The most common reasons for clinical trial ineligibility in our cohort was additional malignancy, thrombocytopenia and poor performance status. In a single institution recurrent glioblastoma cohort, trial participation was associated with improved survival after adjustment of clinical covariates in this cohort.
MODL-16. GLIOBLASTOMA GROWTH IS SHAPED BY INVASION ROUTE-SPECIFIC FUNCTIONAL SIGNATURES
Authors: Cecilia Krona, Emil Rosén, Soumi Kundu, Karl Holmberg Olausson, Ida Larsson, Ludmila Elfineh, Milena Doroszko, Ramy Elgendy, Johan Wickström, Rebecka Jörnsten, Sven Nelander
Journal: Neuro-Oncology (2023)

Abstract One of the defining features of glioblastomas (GBMs) is the capacity for invasive growth along multiple anatomical pathways in the brain. GBM is well-studied on a genetic and molecular level, but clinically relevant and experimentally tractable models of invasive growth are largely lacking. Here, we report an integrated study of patient-matched information, genomic- and molecular profiles with growth in mouse brains to expose treatments and biomarkers associated with glioblastoma invasion and recurrence. In total, 64 patient-derived cell lines (PDCLs) were injected into the striatum of n ≥ 4 mice each. The 45 tumor-forming PDCLs were each scored for 10 distinct growth characteristics (n = 182 mice). The repertoire of phenotypes was highly divergent, and our material included clear cases of perivascular route invasion, white matter route invasion, perineuronal satellitosis, and gliosarcoma. We explored if cellular pathways, monitored by RNA-sequencing, could account for these differences. GSEA highlighted a positive enrichment for highly proliferative proneural tumors characterized by Notch activation, neuronal signaling, and epigenetic gene regulatory programs in the tumor-initiating lines. Transcriptional signatures were also strongly predictive of route-specific invasion. Diffuse invasion was predominantly seen in classical-subtype PDCLs with astrocytic or outer radial glia-like signatures. Proneural PDCLs, in turn, grew as solid tumors with an invasive peripheral region around vasculature, and mesenchymal tumors were more demarcated. To explore the therapeutic implications of our findings, we used our data-driven method (TargetTranslator, Nat Comm 2020) to predict the drug vulnerabilities of different types of invasive glioblastoma. Defined GBM tumors with perivascular invasion are characterized by increased IGFR1, MAPK/ERK, PI3K/AKT/mTOR, and JAK2 signaling. Diffusively growing GBM tumors, on the other hand, depend more on Wnt/β-catenin signaling, neuronal signaling, and active inflammatory response. Using a sphere invasion assay, we confirm that targeting both PI3K- and Wnt signaling selectively reduces glioblastoma invasion, highlighting their therapeutic potential.
DISP-11. PROMINENT FRONTAL BOSSING AND BLINDNESS FOLLOWING SUBTOTAL RESECTION OF LOW-GRADE MENINGIOMA: HIGHLIGHTING HEALTH DISPARITIES
Authors: Jessica White, Sanghee Lim, Bryan Neth, Ivan Carabenciov, Derek Stitt, Rafid Mustafa
Journal: Neuro-Oncology (2023)

Abstract Low-grade meningiomas with subtotal resection carry significantly shorter recurrence-free survival rates than those with gross total resection. We report the natural history of a case of low-grade meningioma after subtotal resection and review the literature. We aim to highlight known global health disparities in oncology treatment by describing a case of meningioma progression following subtotal resection. A 40-year-old Kenyan woman presented locally with headache, nausea, and vision loss over approximately a six month time period. A 5 cm olfactory groove meningioma was discovered, and she subsequently underwent subtotal resection that was likely limited due to hemorrhagic complications. Over the following two years, she developed progressive dizziness, nausea, gait instability, difficulty performing tasks, and visual loss prompting medical evaluation at our institution. Physical examination demonstrated blindness, bilateral proptosis with severe vertical gaze palsy, and prominent frontal bossing. MRI Brain revealed a 9 cm enhancing mass arising from the cribriform plate with elevation of an ununited overlying frontal craniotomy flap and apparent meningoceles extending through the presumed osteotomy bilaterally. She underwent successful resection with pathology demonstrating CNS WHO Grade 1 meningioma. Her postoperative neurologic exam showed subtle improvement, specifically in regards to orientation questions. In this patient, bone flap displacement from prior craniotomy allowed significant interval tumor growth while minimizing mass effect on brain parenchyma. This case highlights global health disparities in low-grade meningioma management related to appropriate healthcare access in underserved patients.